Project Summary Age-related bone loss is an enormous public health problem. While there has been considerable progress in recent years towards a better understanding of the mechanisms of skeletal aging using rodent models, there are major gaps in our understanding of the aging skeleton in humans. In particular, the underlying mechanisms in humans that lead to reduced bone formation with aging remain unknown. Consistent with rodent studies, we recently demonstrated, using direct microneurography, that increased sympathetic outflow in postmenopausal women was associated with impaired bone microarchitecture and reduced serum bone formation markers. Based on these findings, Project 1 will investigate the central theme of this program project grant (PPG), sympathetic nervous system (SNS) control of bone metabolism, by a proof-of-concept interventional study in Aim 1 which will not only provide the pivotal test of the hypothesis that the SNS regulates bone turnover in humans but will also examine the -adrenergic receptor (-AR) selectivity of this effect. In Aim 2, this Project will examine other mechanisms, in addition to -AR signaling, that lead to the impaired bone formation with aging. We have developed novel techniques whereby we can obtain small needle biopsies of bone from humans and rapidly isolate sequential fractions of increasingly enriched human osteoblast and osteocyte populations in which we can interrogate specific gene expression pathways. Thus, the overall goal of this Project is to better define, in vivo in humans, the mechanisms for the age-related defect in bone formation. We will accomplish this goal within the context of our two specific Aims. Aim 1: In postmenopausal women, who have increased sympathetic outflow, to test the hypothesis that treatment with low doses of a non-selective -blocker (propranolol) will increase serum markers of bone formation and reduce markers of bone resorption (Aim 1a); and, to better define the -AR selectivity (1 versus 2) for regulation of bone turnover by sympathetic outflow in humans by using increasingly 1-selective blockers (Aim 1b). Aim 2: In aging women and men, to identify novel mechanisms responsible for the age-related impairment in bone formation by interrogating specific genes and pathways related to bone formation in human osteoblast- and osteocyte- enriched preparations, including known -AR target genes. The studies proposed in this Project are highly integrated with those in the other two Projects. Specifically, the population impact of an important age-related condition associated with increased sympathetic outflow (congestive heart failure) will be examined in Project 2, and Project 3 will use mouse models to examine potential interactions between -AR and estrogen (E) signaling in bone. Further, specific genes and pathways identified as regulated by -AR and E signaling in osteoblast- and osteocyte-enriched cell populations from mouse bones in Project 3 will be evaluated in similar cell populations from young versus elderly humans in this Project. Thus, as in previous cycles of this PPG, Project 1 will provide the central underpinnings for interactions and synergies across the Projects of this PPG.